Suspensions of microparticles are finding increasing application in the pharmaceutical industry for delivery of diagnostic and therapeutic agents. In some cases, it is desirable or necessary to supply a suspension of microparticles in a dry powder form that can be reconstituted to an aqueous system just prior to use. One method of drying an aqueous medium is by lyophilization by which the medium is frozen and then the water is extracted by sublimation under vacuum. If the aqueous medium contains a suspension of microparticles, these microparticles tend to cluster during the initial freezing step of the lyophilization process due to the propagation of the crystallization front. Often, the microparticles become permanently aggregated and do not redisperse when reconstituted. In applications requiring the microparticle suspension to be injected intravenously, the presence of aggregates is unacceptable because of their tendency to become trapped in the capillary bed with potentially deleterious effects.
An excipient for lyophilizing a suspension of microparticles is provided comprising an oil-in-water emulsion consisting of an aqueous phase containing suitable bulking agents, cryoprotectants, and surfactants and an organic phase wherein the organic phase has a freezing point of about or higher than the freezing point of the aqueous phase and which is substantially or completely removed during the lyophilization process. The ratio of the aqueous phase to the organic phase is typically in the range of 80:20 and 30:70 v/v. The concentration of microparticles suspended in the emulsion should be such that the number of emulsion droplets far exceeds the number of microparticles. This will insure that each microparticle is surrounded by a plethora of droplets. The emulsion droplets thus act as a protective colloid preventing direct microparticle to microparticle contact as they are clustered together into aggregates during the freezing step of the lyophilization process. The resulting aggregates would then be composed of the microparticles commingled with the frozen organic phase emulsion droplets.
During the drying steps of the lyophilization process, both the water and organic phases are extracted, leaving a dry cake derived from the aqueous phase solutes. Within the cake are suspended the microparticles surrounded by hollow voids where there previously were the frozen microbeads of the inner organic phase. Since the microparticles are separated from one another by voids, the reconstituted composition is an aqueous suspension of discrete microparticles essentially free of aggregation.
The present invention also provides a method to produce a suspension of microparticles having a lessened tendency to separate from its suspending medium by sedimentation or by creaming. Upon reconstitution the microparticle suspension becomes a purely aqueous system with a viscosity determined solely by the dissolved solutes.